Alzheimer disease is the most common cause of irreversible, chronic dementia. One factor which complicates the interpretation of many clinical research studies is that 20% or more of clinically diagnosed cases do not have Alzheimer disease at autopsy. Although Alzheimer disease may be inherited in less than 10-20% of all cases, the main justification for studying familial cases lies in the accuracy of diagnosis which may be inferred through post-mortem examination of other affected family members. Previous genetic studies have not clarified the role of inheritance. Recent advances in the field of molecular biology have resulted in the development of recombinant DNA technology. Other molecular approaches that are being used to study degenerative neurological disorders include investigations of DNA repair, immunological function and abnormal protein production. In this project skill fibroblast and peripheral blood lymphoblast cultures will be established from members of large kindred with familiar Alzheimer disease. These cultures will serve as a renewable source of DNA and cell lines which can be used for genetic linkage, viability, and biochemical studies. Alzheimer disease may result from a form of primary neuronal degeneration. Neurotransmitter studies suggest that there is a central nervous system degeneration of cholinergic neurons. However, there is substantial evidence which shows that the locus ceruleus, an important noradrenergic nucleus, is also involved as well as other neurotransmitter and peptide systems. In order to define the natural history, temporal progression, and biochemical abnormalities in Alzheimer disease, this project will include a longitudinal study of affected and at-risk subjects from large kindreds with familial Alzheimer disease. Detailed neuropsychological testing, PET scanning, NMR imaging, neurotransmitter studies and pharmacological investigations are planned. Neuropathological and neurochemical studies of post-mortem specimens from these families will also be conducted.